This invention is directed to imidazolyl-cyclic acetals, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of TNF.
Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
The principal in vivo actions of TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of TNF with poor prognosis in sepsis, graft versus host disease and adult respiratory distress syndrome, and its role in many other immunologic processes, this factor is regarded as an important mediator of general inflammation.
TNF primes or activates neutrophils, eosinophils, and endothelial cells to release tissue damaging mediators and increase the expression of adhesion molecules. In fibroblasts, TNF stimulates the production of collagenase, an enzyme implicated in the joint destruction in rheumatoid arthritis. TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatory cytokines such IL-1, IL-6, IL-8 and GM-CSF, which in some cases mediate the end effects of TNF. The ability of TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state. Cytokines such as TNF have been shown to activate HIV replication in monocytes and macrophages. Features of endotoxic shock such as fever, metabolic acidosis, hypotension and intravascular coagulation are thought to be mediated through the actions of TNF. The cachexia associated with certain disease states is mediated through indirect effects on protein catabolism. TNF also promotes bone resorption and acute phase protein synthesis.
TNF-alpha inhibits surfactant protein C gene transcription, which may contribute to abnormalities of surfactant homeostasis associated with pulmonary injury and infection, induces mucin hypersecretion and mediates the recruitment of neutrophils and eosinophils during airway inflammation. Although TNF-alpha inhibits collagen synthesis in fibroblasts, a number of studies point to it being pro-fibrotic in vivo. Thus, by inhibiting TNF-alpha production, the compounds of the invention have potential in suppressing the inflammation and airways remodelling that occurs in asthma.
TNF-alpha inhibits the ability of insulin to stimulate glucose uptake in adipose tissue. In obesity the overproduction of TNF is thought to cause an insulin-resistant state. Thus, by blocking TNF release the compounds of the invention have anti-diabetic potential.
TNF-alpha can induce angiogenesis in normally avascular tissue, possibly through upregulation of other pro-inflammatory cytokines, upregulation of adhesion molecules, stimulation of matrix mettalloproteinase expression and increased prostaglandin production. Thus, inhibition of TNF-alpha release by compounds of the invention will have benefit in angiogenesis dependent diseases including arthritis, diabetic retinopathies and ischemia induced diseases (myocardial infarction) and cancer.
The discussion herein relates to disease states associated with TNF including those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as, but not limited to IL-1 or IL-6, that are modulated by association with TNF. For example, a IL-1 associated disease state, where IL-1 production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF. TNF-alpha and TNF-beta are also herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise, since there is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biological responses and bind to the same cellular receptor.
We have now found a novel group of imidazolyl-cyclic acetals which have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example TNF.
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein:
R1 is optionally substituted heteroaryl;
R2 is optionally substituted aryl or optionally substituted heteroaryl;
R3 represents a group xe2x80x94L1xe2x80x94R7 or xe2x80x94L2xe2x80x94R8 
[where L1 represents a straight- or branched-chain alkylene linkage containing from 1 to about 6 carbon atoms optionally substituted by halogen or oxo; R7 is hydrogen, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, nitro, xe2x80x94S(O)nR9, (where R9 is alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl and n is zero or an integer 1 or 2), xe2x80x94NHSO2R9, xe2x80x94C(xe2x95x90Z)OR10 (where Z is an oxygen or sulphur atom and R10 is hydrogen or R9), xe2x80x94C(xe2x95x90Z)R10, xe2x80x94OR10, xe2x80x94N(R11)xe2x80x94C(xe2x95x90Z)R9 (where R11 is hydrogen or alkyl), xe2x80x94NY1Y2 {where Y1 and Y2 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, heteroaryl or heteroarylalkyl, or the group xe2x80x94NY1 Y2 may form a 5-7 membered cyclic amine which may optionally contain a further heteroatom selected from O, S, or NY3 (where Y3 is hydrogen, alkyl, aryl, arylalkyl, xe2x80x94CHO, xe2x80x94C(xe2x95x90Z)R9 or xe2x80x94SO2R9), or which may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system}, xe2x80x94SO2xe2x80x94NY1Y2, xe2x80x94C(xe2x95x90Z)xe2x80x94NY1Y2, xe2x80x94N(R11)xe2x80x94C(xe2x95x90Z)xe2x80x94NY1Y2, xe2x80x94N(OR10)xe2x80x94C(xe2x95x90Z)xe2x80x94NY1Y2, xe2x80x94N(OR10)xe2x80x94C(xe2x95x90Z)R10, xe2x80x94C(xe2x95x90NOR10)R10, xe2x80x94C(xe2x95x90Z)NR10OR12 (where R12 is hydrogen, alkyl, aryl or arylalkyl), xe2x80x94N(R11)xe2x80x94C(xe2x95x90NR13)xe2x80x94NY1Y2 (where R13 is hydrogen, cyano, alkyl, cycloalkyl or aryl), or xe2x80x94N(R11)xe2x80x94C(xe2x95x90Z)OR11; L2 represents a direct bond or a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms and contains a double or triple carbon-carbon bond; and R8 is hydrogen, aryl, cycloalkenyl, cycloalkyl, heteroaryl or heterocycloalkyl];
R4 represents a group xe2x80x94L3xe2x80x94R14 
[where L3 represents a direct bond or a straight- or branched-chain alkylene linkage containing from 1 to about 6 carbon atoms (optionally substituted by halogen, hydroxy, alkoxy or oxo); and R14 is hydrogen, alkyl, azido, hydroxy, alkoxy, aryl, arylalkyloxy, aryloxy, carboxy (or an acid bioisostere), cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, nitro, xe2x80x94NY4Y5, {where Y4 and Y5 are independently hydrogen, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or alkyl optionally substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, xe2x80x94CO2R10, xe2x80x94CONY1Y2 or xe2x80x94NY1Y2, or the group xe2x80x94NY4Y5 may form a 5-7 membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5, 6,or 7 membered cyclic acetal derivative thereof), R9 or alkyl substituted by carboxy, carboxamido or hydroxy (ii) may also contain a further heteroatom selected from O, S, SO2 or NY6 (where Y6 is hydrogen, alkyl, aryl, arylalkyl, xe2x80x94C(xe2x95x90Z)R9, xe2x80x94C(xe2x95x90Z)OR9 or xe2x80x94SO2R9) and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system}, xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15 (where R15 is alkyl, alkoxy, aryl, arylalkyloxy, cycloalkyl, heteroaryl, heteroarylalkoxy or heterocycloalkyl); xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16 (where R16 is alkoxy, aryl, arylalkyl arylalkyloxy carbonylamino, carboxy (or an acid bioisostere), cycloalkyl, cyano, halo, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxy or xe2x80x94NY1Y2, and L4 is a straight- or branched-chain alkylene linkage containing from 1 to about 6 carbon atoms), xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94R15, xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94L4xe2x80x94R16, xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15, xe2x80x94N(R10)xe2x80x94SO2xe2x80x94L4xe2x80x94R16, xe2x80x94S(O)nR9, xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5 or xe2x80x94C(xe2x95x90Z)xe2x80x94OR9];
R5 represents hydrogen, alkyl or hydroxyalkyl; or
R4 and R5, when attached to the same carbon atom, may form with the said carbon atom a cycloalkyl, cycloalkenyl or heterocycloalkyl ring or a group Cxe2x95x90CH2;
R6 represents hydrogen or alkyl; and
m is zero or an integer 1 or 2;
and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (I) and N-oxides thereof, and their prodrugs.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the N-oxides, the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their N-oxides, salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
It will be appreciated that when m is zero the cyclic acetal system in formula (I) represents a 1,3-dioxolane ring; when m is 1 the cyclic acetal system in formula (I) represents a 1,3-dioxane; and when m is 2 the cyclic acetal system in formula (I) represents a 1,3-dioxepane.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993, 33, pages 576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995, pages 34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995, 343, pages 105-109 xe2x80x9cTheoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. xe2x80x9cBranchedxe2x80x9d, as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxymethylxe2x80x9d means an alkyl-Oxe2x80x94CH2xe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxymethyl groups include methoxymethyl and ethoxymethyl.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. Exemplary alkyl groups for R5, R6 and within R4 include C1-4alkyl groups such as methyl, ethyl, n-propyl and i-propyl.
xe2x80x9cAlkylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain having from 1 to about 15 carbon atoms. Particular alkylene groups are the lower alkylene groups having from 1 to about 6 carbon atoms. Exemplary groups include methylene and ethylene.
xe2x80x9cAlkylsulphinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y7Y8Nxe2x80x94, Y7Y8NCOxe2x80x94, Y7Y8NSO2xe2x80x94(where Y7 and Y8 are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl), Y7Y8Nxe2x80x94C2-6alkylene-Z2xe2x80x94 (where Z2 is O, NR5 or S(O)n), alkylC(xe2x95x90O)xe2x80x94Y7Nxe2x80x94, alkylSO2xe2x80x94Y7Nxe2x80x94 or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or Y7Y8Nxe2x80x94. Preferred aryl group substituents within R2 include halogen, alkoxy, trifluoromethyl, alkylthio, alkylsulphinyl, Y7Y8Nxe2x80x94, alkylC(xe2x95x90O)xe2x80x94Y7Nxe2x80x94 or alkylSO2xe2x80x94Y7Nxe2x80x94, more preferably fluoro.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkylxe2x80x94 group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulphinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen. Examples of optionally substituted azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, and benzimidazolyl, optionally substituted with one or more xe2x80x9cheteroaryl group substituentsxe2x80x9d. Preferred azaheteroaryl groups within R1 include optionally substituted pyridyl and pyrimidinyl. Preferred heteroaryl group substituents when R1 is pyrimidinyl include R17Z3xe2x80x94 [where R17 is alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, xe2x80x94CO2R10, xe2x80x94CONY1Y2 orxe2x80x94NY4Y5 and Z3 is O or S(O)n] and Y4Y5Nxe2x80x94.
xe2x80x9cCycloalkenylxe2x80x9d means an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 5 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cyclopentenyl. Exemplary multicyclic cycloalkenyl ring include norbornenyl. The cycloalkenyl group may be substituted by one or more substituents chosen from, for example, halo, or alkyl.
xe2x80x9cCycloalkoxymethylxe2x80x9d means a cycloalkyl-Oxe2x80x94CH2-group in which the cycloalkyl group is as described hereinafter. Exemplary cycloalkoxymethyl groups include cyclopropyloxymethyl and cyclopentyloxymethyl.
xe2x80x9cCycloalkylxe2x80x9d means an optionally substituted non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Exemplary multicyclic cycloalkyl rings include perhydronaphthyl, adamant-(1- or 2-)yl and norbornyl and spirocyclic groups e.g. spiro[4,4]non-2yl. When R3 is, or contains, a cycloalkyl ring this may particularly represent a 3 to 7 membered monocyclic ring, especially cyclohexyl. The cycloalkyl group may be substituted by one or more (e.g. 1, 2, or 3) substituents chosen from, for example, alkyl, aryl, arylalkyl, halo, halo substituted alkyl (such as trifluoromethyl), hydroxyalkyl, hydroxy, alkoxy, xe2x80x94S(O)n-alkyl, xe2x80x94NY1Y2 or xe2x80x94CO2R12.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkylxe2x80x94 group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyl-Oxe2x80x94 group in which the cycloalkyl group is as described herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-COxe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroaroylaminoxe2x80x9d means a heteroaroyl-NHxe2x80x94 group in which the heteroaroyl moiety is as previously described.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur. Examples of suitable optionally substituted heteroaryl groups include benzimidazolyl, furyl, imidazolyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. When R1 is an optionally substituted heteroaryl group this may particularly represent an optionally substituted xe2x80x9cazaheteroarylxe2x80x9d group. Heteroaryl groups may be substituted with one or more heteroaryl group substituents which may be the same or different, where xe2x80x9cheteroaryl group substituentxe2x80x9d includes, for example acyl, acylamino, alkoxycarbonyl, alkylenedioxy, aroyl, aroylamino, aryl, arylalkyloxycarbonyl, aryloxycarbonyl, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroaroylamino, hydroxy, nitro, trifluoromethyl, R17Z3xe2x80x94, Y4Y5Nxe2x80x94, Y4Y5Nxe2x80x94COxe2x80x94, Y4Y5NSO2xe2x80x94, alkylSO2xe2x80x94Y4Nxe2x80x94 or alkyl optionally substituted with aryl, heteroaryl, hydroxy, oxo, xe2x80x94CO2R10, xe2x80x94CONY1Y2 or Y4Y5Nxe2x80x94.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkylxe2x80x94 group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylsulphonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocycloalkylxe2x80x9d means a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY3. Exemplary heterocycloalkyl groups include 5-7 membered cyclic ethers such as tetrahydrofuran and perhydropyran.
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkylxe2x80x94 group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cHeterocycloalkyloxyxe2x80x9d means a heterocycloalkyl-Oxe2x80x94 group in which the heterocycloalkyl is as previously defined.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkylxe2x80x94 group in which alkyl is as previously defined. Preferred hydroxyalkyl groups contain C1-4alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cY7Y8Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein Y7 and Y8 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino. xe2x80x9cY7Y8NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein Y7 and Y8 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cY7Y8NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulphamoyl group, wherein Y7 and Y8 are as previously described. Exemplary groups are sulphamoyl (H2NSO2xe2x80x94) and dimethylsulphamoyl (Me2NSO2xe2x80x94).
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, iseth ionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
Suitable esters of compounds of formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent optionally substituted azaheteroaryl such as optionally substituted pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl or benzimidazolyl (for example optionally substituted 4-pyridyl, 4-pyrimidinyl, 4-quinolinyl, 6-isoquinolinyl, 4-quinazolinyl, 1-imidazolyl or 1-benzimidazolyl). R1 is preferably optionally substituted 4-pyridyl or 4-pyrimidinyl, especially unsubstituted 4-pyridyl or 2-substituted 4-pyrimidinyl. Preferred substituents include C1-4alkyl, especially methyl, xe2x80x94NY4Y5 (especially where at least one of Y4 and Y5 is hydrogen) or xe2x80x94OR17 (especially where R17 is cycloalkyl).
R2 is preferably optionally substituted phenyl, particularly when substituted by halogen, especially fluoro and chloro, or an alkylthio or alkylsulphinyl group, especially methylthio or methysulphinyl, or a trifluoromethyl group. R2 is more preferably phenyl substituted by a halogen (e.g. fluorine) atom, especially in the 4-position.
R3 may particularly represent hydrogen or C1-4alkyl, preferably hydrogen.
R4 may particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94NY4Y5, where Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, in which Z, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, R10 is hydrogen and R15 is alkyl (especially methyl), aryl (e.g. substituted or more preferably, unsubstituted phenyl) or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, in which Z, L4, R10 and R16 are as defined hereinbefore, especially where Z is oxygen, L4 is methylene, R10 is hydrogen, and R16 is aryl (e.g. substituted or more preferably, unsubstituted phenyl) or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, in which Z is as defined hereinbefore, especially oxygen, and Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen or where Y4 is hydrogen and Y5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, in which Z is as defined hereinbefore, especially oxygen, and the group xe2x80x94NY4Y5 forms a 5-7 membered cyclic amine [which may optionally contain a further heteroatom selected from O, S or NY6 (where Y6 is as defined hereinbefore)], preferably a 5-7 membered cyclic amine optionally containing oxygen, especially a morpholine ring.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94OR9, in which Z and R9 are as defined hereinbefore, especially where Z is oxygen and R9 is C1-4alkyl, preferably methyl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond, especially methylene or ethylene, and R14 is alkyl, especially methyl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is hydroxy.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, in which Z, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, R10 is hydrogen and R15 is alkyl, aryl or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, in which Z, L4, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, L4 is C1-6alkylene, especially methylene, R10 is hydrogen and R16 is aryl or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94NHC(xe2x95x90Z)xe2x80x94NHxe2x80x94R15, in which Z and R15 are as defined hereinbefore, especially where R15 is alkyl, aryl or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94L4xe2x80x94R16, in which Z, L4 and R16 are as defined hereinbefore, especially where L4 is methylene and R15 is aryl or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially C1-3alkylene, preferably methylene, and R14 is xe2x80x94NY4Y5, where Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene or ethylene, and R14 is aryl or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15, in which R10 and R15 are as defined hereinbefore, especially where R10 is hydrogen and R15 is alkyl, aryl or heteroaryl.
R4 may also particularly represent a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94SO2xe2x80x94L4xe2x80x94R15, in which L4, R10 and R15 are as defined hereinbefore, especially where L4 is methylene, R10 is hydrogen and R15 is alkyl, aryl or heteroaryl.
R5 may particularly represent hydrogen or C1-4alkyl, especially methyl.
R5 may also particularly represent hydroxyalkyl, especially hydroxymethyl.
R4 and R5 together with the carbon atom to which they are attached may particularly represent a group Cxe2x95x90CH2 or a 5-7 membered cyclic ether such as tetrahydrofuran-2-yl or perhydropyran-2-yl.
R6 may particularly represent hydrogen or C1-4alkyl, especially hydrogen.
m is preferably an integer 1.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular group of compounds of the invention are compounds of formula (Ia): 
in which R4 and R5 are as hereinbefore defined, and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ia) and N-oxides thereof, and their prodrugs.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94NY4Y5, where Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen, are preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, in which Z, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, R10 is hydrogen and R15 is alkyl (especially methyl), aryl (e.g. substituted or more preferably, unsubstituted phenyl) or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, in which Z, L4, R10 and R16 are as defined hereinbefore, especially where Z is oxygen, L4 is methylene, R10 is hydrogen, and R16 is aryl (e.g. substituted or more preferably, unsubstituted phenyl) or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, in which Z is as defined hereinbefore, especially oxygen, and Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen or where Y4 is hydrogen and Y5 is aryl, heteroaryl or heteroarylalkyl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, in which Z is as defined hereinbefore, especially oxygen, and the group xe2x80x94NY4Y5 forms a 5-7 membered cyclic amine [which may optionally contain a further heteroatom selected from O, S or NY6 (where Y6 is as defined hereinbefore)], preferably a 5-7 membered cyclic amine optionally containing oxygen, especially a morpholine ring, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94OR9, in which Z and R9 are as defined hereinbefore, especially where Z is oxygen and R9 is C1-4alkyl, preferably methyl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond, especially methylene or ethylene, and R14 is alkyl, especially methyl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is hydroxy, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, in which Z, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, R10 is hydrogen and R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, in which Z, L4, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, L4 is C1-6alkylene, especially methylene, R10 is hydrogen and R16 is aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94R15, in which Z and R15 are as defined hereinbefore, especially where R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94L4xe2x80x94R16, in which Z, L4 and R16 are as defined hereinbefore, especially where L4 is methylene and R15 is aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially C1-3alkylene, preferably methylene, and R14 is xe2x80x94NY4Y5, where Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene or ethylene, and R14 is aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15, in which R10 and R15 are as defined hereinbefore, especially where R10 is hydrogen and R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94SO2xe2x80x94L4xe2x80x94R15, in which L4, R10 and R15 are as defined hereinbefore, especially where L4 is methylene, R10 is hydrogen and R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ia) in which R5 represents hydrogen, C1-4alkyl (e.g. methyl) or hydroxyC1-4alkyl (e.g. hydroxymethyl), especially methyl, are preferred.
Compounds of formula (Ia) in which R4 and R5 together with the carbon atom to which they are attached represent a group Cxe2x95x90CH2 or a 5-7 membered cyclic ether such as tetrahydrofuran-2-yl or perhydropyran-2-yl are also preferred.
A preferred group of compounds of the invention are compounds of formula (Ia) in which R4 is a group xe2x80x94L3xe2x80x94R14 {where L3 is a direct bond and R14 is (i) xe2x80x94NY4Y5, preferably xe2x80x94NH2; (ii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)-alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)-heteroaryl, especially xe2x80x94NHxe2x80x94C(xe2x95x90O)-aryl, particularly where aryl is substituted, or more preferably, unsubstituted phenyl; (iii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-heteroaryl, particularly where aryl is substituted, or more preferably, unsubstituted phenyl; (iv) xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NH2; (v) xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NY4Y5 where the group xe2x80x94NY4Y5 forms a 5-7 membered cyclic amine [which may optionally contain a further heteroatom selected from O, S or NY6 (where Y6 is as defined hereinbefore), preferably a 5-7 membered cyclic amine optionally containing oxygen, especially a morpholine ring]; (vi) xe2x80x94C(xe2x95x90Z)OR9, particularly xe2x80x94CO2Me; or (vii) alkyl, especially methyl} and R5 represents hydrogen, C1-4alkyl (e.g. methyl) or hydroxyC1-4alkyl (e.g. hydroxymethyl), especially methyl; and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ia) herein and N-oxides thereof, and their prodrugs.
A further preferred group of compounds of formula (Ia) are compounds in which R4 is a group xe2x80x94L3xe2x80x94R14 {where L3 is a methylene linkage and R14 is (i) hydroxy; (ii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O-alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)-heteroaryl; (iii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-heteroaryl; (iv) xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94R15 preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH-heteroaryl;(v) NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94L4xe2x80x94R16 preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2-alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2-heteroaryl; (vi) xe2x80x94NY4Y5, preferably xe2x80x94NH2; (vii) aryl; (viii) heteroaryl; (ix) xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15, preferably xe2x80x94NHxe2x80x94SO2-alkyl, NHxe2x80x94SO2-aryl or xe2x80x94NHxe2x80x94SO2-heteroaryl} and R5 represents hydrogen, C1-4alkyl (e.g. methyl) or hydroxyC1-4alkyl (e.g. hydroxymethyl), especially methyl; and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ia) herein and N-oxides thereof, and their prodrugs.
A further particular group of compounds of the invention are compounds of formula (Ib): 
in which R4 and R5 are as hereinbefore defined, and R18 is R17Z3xe2x80x94 or Y4Y5Nxe2x80x94 (in which R17, Y4, Y5 and Z3 are as hereinbefore defined), and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ib) and N-oxides thereof, and their prodrugs.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94NY4Y5, where Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen, are preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, in which Z, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, R10 is hydrogen and R15 is alkyl (especially methyl), aryl (e.g. substituted or more preferably, unsubstituted phenyl) or heteroaryl, are also preferred.
Compounds, of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, in which Z, L4, R10 and R16 are as defined hereinbefore, especially where Z is oxygen, L4 is methylene, R10 is hydrogen, and R16 is aryl (e.g. substituted or more preferably, unsubstituted phenyl) or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, in which Z is as defined hereinbefore, especially oxygen, and Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen or where Y4 is hydrogen and Y5 is aryl, heteroaryl or heteroarylalkyl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, in which Z is as defined hereinbefore, especially oxygen, and the group xe2x80x94NY4Y5 forms a 5-7 membered cyclic amine [which may optionally contain a further heteroatom selected from O, S or NY6 (where Y6 is as defined hereinbefore)], preferably a 5-7 membered cyclic amine optionally containing oxygen, especially a morpholine ring, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond and R14 is xe2x80x94C(xe2x95x90Z)xe2x80x94OR9, in which Z and R9 are as defined hereinbefore, especially where Z is oxygen and R9 is C1-4alkyl, preferably methyl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is a direct bond, especially methylene or ethylene, and R14 is alkyl, especially methyl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is hydroxy, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, in which Z, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, R10 is hydrogen and R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, in which Z, L4, R10 and R15 are as defined hereinbefore, especially where Z is oxygen, L4 is C1-6alkylene, especially methylene, R10 is hydrogen and R16 is aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94R15, in which Z and R15 are as defined hereinbefore, especially where R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94L4xe2x80x94R16, in which Z, L4 and R16 are as defined hereinbefore, especially where L4 is methylene and R15 is aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially C1-3alkylene, preferably methylene, and R14 is xe2x80x94NY4Y5, where Y4 and Y5 are as defined hereinbefore, especially where Y4 and Y5 are hydrogen, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene or ethylene, and R14 is aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15, in which R10 and R15 are as defined hereinbefore, especially where R10 is hydrogen and R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R4 represents a group xe2x80x94L3xe2x80x94R14 where L3 is C1-6alkylene, especially methylene, and R14 is xe2x80x94N(R10)xe2x80x94SO2xe2x80x94L4xe2x80x94R15, in which L4, R10 and R15 are as defined hereinbefore, especially where L4 is methylene, R10 is hydrogen and R15 is alkyl, aryl or heteroaryl, are also preferred.
Compounds of formula (Ib) in which R5 represents hydrogen, C1-4alkyl (e.g. methyl) or hydroxyC1-4alkyl (e.g. hydroxymethyl), especially methyl, are preferred.
Compounds of formula (Ib) in which R4 and R5 together with the carbon atom to which they are attached represent a group Cxe2x95x90CH2 or a 5-7 membered cyclic ether such as tetrahydrofuran-2-yl or perhydropyran-2-yl are also preferred.
Compounds of formula (Ib) in which R18 is xe2x80x94NY4Y5, where Y4 and Y5 are as hereinbefore defined, especially where Y4 is hydrogen and Y5 is (i) arylalkyl, particularly optionally substituted benzyl or optionally substituted xcex1-methylbenzyl (in which the phenyl group may be optionally substituted by one or more aryl group substituents, especially halo, methoxy, trifluoromethyl, methyl and methylenedioxy); (ii) heteroarylalkyl, particularly azaheteroaryl-alkyl, more particularly azaheteroaryl-CH2xe2x80x94; (iii) C2-6alkyl substituted by alkoxy, particularly C2-6alkyl substituted by methoxy; (iv) C2-6alkyl substituted by xe2x80x94NY1Y2, particularly C2-6alkyl substituted by xe2x80x94NMe2; (v) C2-6alkyl substituted by hydroxy; (vi) cycloalkyl or (vii) aryl, especially phenyl optionally substituted by one or more aryl group substituents, especially halo, methoxy, trifluoromethyl, methyl or methylenedioxy; are preferred.
Compounds of formula (Ib) in which R18 is xe2x80x94OR17, where R17 is as hereinbefore defined, especially where R17 is alkyl, aryl (especially phenyl optionally substituted by one or more aryl group substituents, especially halo, methoxy, trifluoromethyl, methyl or methylenedioxy) or cycloalkyl, are also preferred.
A preferred group of compounds of the invention are compounds of formula (Ib) in which R4 is a group xe2x80x94L3xe2x80x94R14 {where L3 is a direct bond and R14 is (i) xe2x80x94NY4Y5, preferably xe2x80x94NH2; (ii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)-alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)-heteroaryl, especially xe2x80x94NHxe2x80x94C(xe2x95x90O)-aryl, particularly where aryl is substituted, or more preferably, unsubstituted phenyl; (iii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4xe2x80x94R16, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-heteroaryl, particularly where aryl is substituted, or more preferably, unsubstituted phenyl; (iv) xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NH2; (v) xe2x80x94C(xe2x95x90Z)xe2x80x94NY4Y5, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NY4Y5 where the group xe2x80x94NY4Y5 forms a 5-7 membered cyclic amine [which may optionally contain a further heteroatom selected from O, S or NY6 (where Y6 is as defined hereinbefore), preferably a 5-7 membered cyclic amine optionally containing oxygen, especially a morpholine ring]; (vi) xe2x80x94C(xe2x95x90Z)OR9, particularly xe2x80x94CO2Me; or (vii) alkyl, especially methyl} R5 represents hydrogen, C1-4alkyl (e.g. methyl) or hydroxyC1-4alkyl (e.g. hydroxymethyl), especially methyl and R18 represents xe2x80x94NY4Y5 {where Y4 and Y5 are as hereinbefore defined, especially where Y4 is hydrogen and Y5 is (i) arylalkyl, particularly benzyl or xcex1-methylbenzyl; (ii) heteroarylalkyl, particularly azaheteroaryl-alkyl, more particularly azaheteroaryl-CH2xe2x80x94; (iii) C2-6alkyl substituted by alkoxy, particularly C2-6alkyl substituted by methoxy; (iv) C2-6alkyl substituted by xe2x80x94NY1Y2, particularly C2-6alkyl substituted by xe2x80x94NMe2; (v) C2-6alkyl substituted by hydroxy; (vi) cycloalkyl or (vii) aryl, especially phenyl optionally substituted by one or more aryl group substituents, especially halo, methoxy, trifluoromethyl, methyl or methylenedioxy} or xe2x80x94OR17, where R17 is alkyl or cycloalkyl; and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ia) herein and N-oxides thereof, and their prodrugs.
A further preferred group of compounds of formula (Ib) are compounds in which R4 is a group xe2x80x94L3xe2x80x94R14 {where L3 is a methylene linkage and R14 is (i) hydroxy; (ii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94R15, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)-alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)-heteroaryl; (iii) xe2x80x94N(R10)xe2x80x94C(xe2x95x90Z)xe2x80x94L4-R16, preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2-heteroaryl; (iv) xe2x80x94NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94R15 preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH-heteroaryl;(v) NHxe2x80x94C(xe2x95x90Z)xe2x80x94NHxe2x80x94L4xe2x80x94R16 preferably xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2-alkyl, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2-aryl or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2-heteroaryl; (vi) xe2x80x94NY4Y5, preferably xe2x80x94NH2; (vii) aryl; (viii) heteroaryl; (ix) xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15, preferably xe2x80x94NHxe2x80x94SO2-alkyl, NHxe2x80x94SO2-aryl or xe2x80x94NHxe2x80x94SO2-heteroaryl} and R5 represents hydrogen, C1-4alkyl (e.g. methyl) or hydroxyC1-4alkyl (e.g. hydroxymethyl), especially methyl and R18 represents xe2x80x94NY4Y5 {where Y4 and Y5 are as hereinbefore defined, especially where Y4 is hydrogen and Y5 is (i) arylalkyl, particularly benzyl or xcex1-methylbenzyl; (ii) heteroarylalkyl, particularly azaheteroarylalkyl, more particularly azaheteroaryl-CH2xe2x80x94; (iii) C2-6alkyl substituted by alkoxy, particularly C2-6alkyl substituted by methoxy; (iv) C2-6alkyl substituted by xe2x80x94NY1Y2, particularly C2-6alkyl substituted by xe2x80x94NMe2; (v) C2-6alkyl substituted by hydroxy; or (vi) cycloalkyl} or xe2x80x94OR17, where R17 is alkyl or cycloalkyl; and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (la) herein and N-oxides thereof, and their prodrugs.
A particular group of compounds of the invention are those selected from the following:
{2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, cis-isomer, (Compound A);
{2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, trans-isomer, (Compound B);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyridine, (Compound C);
C-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-methylamine, cis- and trans-isomers, (Compound D);
2,2,2-trifluoro-N-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-acetamide, cis- and trans-isomers, (Compound E);
2,2,2-trifluoro-N-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-acetamide, cis-isomer, (Compound F);
2,2,2-trifluoro-N-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-acetamide, trans-isomer, (Compound G);
4-[2-(5-azidomethyl-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyridine, cis- and trans-isomers, (Compound H);
4-[2-(5-benzyl-[1,3]dioxan-2-yl)-5-(4-fluorophenyl)-1H-imidazol-4-yl]-pyridine, cis- adn trans-isomers, (Compound I);
2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid methyl ester, cis- and trans-isomers, (Compound J);
4-[5-(4-fluoro-phenyl)-2-(1,8,10-trioxa-spiro[5.5]undec-9-yl)-1H-imidazol-4-yl]-pyridine, (Compound K);
4-[5-(4-fluoro-phenyl)-2-(1,7,9-trioxa-spiro[4.5]dec-8-yl)-1H-imidazol-4-yl]-pyridine, (Compound L);
4-[2-(5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine, (Compound M);
4-[5-(4-fluoro-phenyl)-2-(5-methylene-[1,3]dioxan-2-yl)-3H-imidazol-4-yl]-pyridine, (Compound N);
4-[2-[1,3]dioxan-2-yl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine, (Compound O);
4-[5-(4-fluoro-phenyl)-2-(4-methyl-[1,3]dioxan-2-yl)-3H-imidazol-4-yl]-pyridine, (R/S)(R/S) isomers, (Compound P);
4-[2-(4,6-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine, (R/S)(R/S)(R/S) isomers, (Compound Q);
4-[2-(5-benzyloxy-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine, cis- and trans-isomers, (Compound R);
4-[5-(4-fluoro-phenyl)-2-(5-phenyl-[1,3]dioxan-2-yl)-3H-imidazol-4-yl]-pyridine, (Compound S);
4-[5-(4-fluoro-phenyl)-2-(4-isopropyl-5,5-dimethyl-[1,3]dioxan-2-yl)-3H-imidazol-4-yl]-pyridine, (R/S)(R/S) isomers, (Compound T);
4-[2-(5,5-diethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine, (Compound U);
4-[2-(2,4-dioxa-spiro[5.5]undec-8-en-3-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine, cis- and trans-isomers, (Compound V);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-benxamide, cis- and trans-isomers, (Compound W);
1-(4-fluoro-phenyl)-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-thiourea, cis- and trans-isomers, (Compound X);
1-(2,6-dimethyl-phenyl)-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-thiourea, cis- and trans-isomers, (Compound Y);
4-[5-(4-fluoro-phenyl)-2-(5-methyl-5-pyrrol-1-yl-[1,3]dioxan-2-yl)-1H-imidazol-4-yl]-pyridine, cis- and trans-isomer, (Compound Z);
C-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-methylamine, trans-isomer, (Compound AA);
C-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-methylamine, cis-isomer, (Compound AB);
2,2,2-trifluoro-N-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylmethyl]-acetamide, trans-isomer, (Compound AC);
2,2,2-trifluoro-N-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylmethyl]-acetamide, cis-isomer, (Compound AD);
5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ulamine, cis-isomer, (Compound AE);
5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylamine, trans-isomer, (Compound AF);
5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylamine, cis- and trans-isomers, (Compound AG);
2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid, trans-isomer, (Compound AH);
2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid, cis-isomer, (Compound AI);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid benzylamide, cis-isomer, (Compound AJ);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid benzylamide, trans-isomer, (Compound AK);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-hydroxy-ethyl)-amide, trans-isomer, (Compound AL);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-methoxy-ethyl)-amide, trans-isomer, (Compound AM);,
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid amide, trans-isomer, (Compound AN);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (pyridin-2-ylmethyl)-amide, trans-isomer, (Compound AO);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (pyridin-3-ylmethyl)-amide, trans-isomer, (Compound AP);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (pyridin-4-ylmethyl)-amide, trans-isomer, (Compound AQ);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-(4-methyl-piperazin-1-yl)-methanone, trans-isomer, (Compound AR);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (3-dimethylamino-propyl)-amide, trans-isomer, (Compound AS);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-amide, trans-isomer, (Compound AT);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (3-hydroxy-propyl)-amide, trans-isomer, (Compound AU);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide, trans-isomer, (Compound AV);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound AW);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-pyrrolidin-1-yl-methanone, trans-isomer, (Compound AX);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid butylamide, trans-isomer, (Compound AY);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid dipropylamide, trans-isomer, (Compound AZ);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (3-methoxy-propyl)-amide, trans-isomer, (Compound BA);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid phenethyl-amide, trans-isomer, (Compound BB);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide, trans-isomer, (Compound BC);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (furan-2-ylmethyl)-amide, trans-isomer, (Compound BD);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound BE);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid dimethylamide, trans-isomer, (Compound BF);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid propylamide, trans-isomer, (Compound BG);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid cyclopropylamide, trans-isomer, (Compound BH);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid cyclopentylamide, trans-isomer, Compound BI);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid cyclohexylamide, trans-isomer, (Compound BJ);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-methoxy-ethyl)-amide, cis-isomer, (Compound BK);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-hydroxy-ethyl)-amide, cis-isomer, (Compound BL);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid amide, cis-isomer, (Compound BM);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (pyridin-2-ylmethyl)-amide, cis-isomer, (Compound BN);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (pyridin-3-ylmethyl)-amide, cis-isomer, (Compound BO);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (pyridin-4-ylmethyl)-amide, cis-isomer, (Compound BP);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, cis-isomer, (Compound BQ);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-(4-methyl-piperazin-1-yl)-methanone, cis-isomer, (Compound BR);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (3-dimethylamino-propyl)-amide, cis-isomer, (Compound BS);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-amide, cis-isomer, (Compound BT);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (3-hydroxy-propyl)-amide, cis-isomer, (Compound BU);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid phenethyl-amide, cis-isomer, (Compound BV);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (3-methoxy-propyl)-amide, cis-isomer, (Compound BW);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide, cis-isomer, (Compound BX);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (furan-2-ylmethyl)-amide, cis-isomer, (Compound BY);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide, cis-isomer, (Compound BZ);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-pyrrolidin-1-yl-methanone, cis-isomer, (Compound CA);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-piperidin-1-yl-methanone, cis-isomer, (Compound CB);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid propylamide, cis-isomer, (Compound CC);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid butylamide, cis-isomer, (Compound CD);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid cyclopropylamide, cis-isomer, (Compound CE);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid cyclopentylamide, cis-isomer, (Compound CF);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid cyclohexylamide, cis-isomer, (Compound CG);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid methylamide, cis-isomer, (Compound CH);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (2-dimethylamino-ethyl)-amide, cis-isomer, (Compound CI);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid dimethylamide, cis-isomer, (Compound CJ);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid dipropylamide, cis-isomer, (Compound CK);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid ethylamide, cis-isomer, (Compound CL);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid methylamide, trans-isomer, (Compound CM);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid dimethylamino-ethyl)-amide, trans-isomer, (Compound CN);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid ethylamide, trans-isomer, (Compound CO);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-phenyl-urea, cis-isomer, (Compound CP);
1-ethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-urea, cis-isomer, (Compound CQ);
1-(3,5-dimethyl-isoxazol-4-yl)-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5methyl-[1,3]dioxan-5-yl}-urea, cis-isomer, (Compound CR);
1-benzyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-urea, cis-isomer, (Compound CS);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-(2-yl-ethyl)-urea, cis-isomer, (Compound CT);
1-(3-acetyl-phenyl)-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-urea, cis-isomer, (Compound CU);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-phenyl-urea, trans-isomer, (Compound CV);
3-(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-ureido)-benzoic acid, trans-isomer, (Compound CW);
1-benzyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-urea, trans-isomer, (Compound CX);
1-ethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-urea, trans-isomer, (Compound CY);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-(2-thiophen-2-yl-ethyl)-urea, trans-isomer, (Compound CZ);
1-benzyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-urea, cis-isomer, (Compound DA);
1-ethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-urea, cis-isomer, (Compound DB);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-phenyl-urea, cis-isomer, (Compound DC);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-phenyl-urea, trans-isomer, (Compound DD);
1-benzyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-urea, trans-isomer, (Compound DE);
1-ethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-urea, trans-isomer, (Compound DF);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-(2-morpholin-4-yl-ethyl)-thiourea, cis-isomer, (Compound DG);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-furan-3-ylmethyl-thiourea, cis-isomer, (Compound DH);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-3-pyridin-3-yl-thiourea, cis-isomer, (Compound DI);
1-benzo[1,3]dioxol-5-yl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-thiourea, cis-isomer, (Compound DJ);
1-benzo[1,3]dioxol-5-ylmethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-thiourea, cis-isomer, (Compound DK);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-pyridin-3-yl-thiourea, trans-isomer, (Compound DL);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-(2-morpholin-4-yl-ethyl)-thiourea, trans-isomer, (Compound DM);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-furan-2-ylmethyl-thiourea, trans-isomer, (Compound DN);
1-benzo[1,3]dioxol-5-ylmethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-thiourea, trans-isomer, (Compound DO);
1-benzo[1,3]dioxol-5-yl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-thiourea, cis-isomer, (Compound DP);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-furan-2-ylmethyl-thiourea, cis-isomer, (Compound DQ);
3-(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-thioureido)-benzoic acid, cis-isomer, (Compound DR);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-pyridin-3-yl-thiourea, cis-isomer, (Compound DS);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-3-(2-morpholin-4-yl-ethyl)-thiourea, cis-isomer, (Compound DT);
1-benzo[1,3]dioxol-5-ylmethyl-3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-thiourea, cis-isomer, (Compound DU);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, cis-isomer, (Compound DV);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-2-phenyl-acetamide, cis-isomer, (Compound DW);
cyclohexanecarboxylic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-amide, cis-isomer, (Compound DX);
2-benzyloxy-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, trans-isomer, (Compound DY);
2-benzyloxy-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, cis-isomer, (Compound DZ);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, trans-isomer, (Compound EA);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-2-phenyl-acetamide, trans-isomer, (Compound EB);
cyclohexanecarboxylic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-amide, trans-isomer, (Compound EC);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-2-phenyl-acetamide, cis-isomer, (Compound ED);
2-benzyloxy-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-acetamide, cis-isomer, (Compound EE);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-2-phenyl-acetamide, cis-isomer, (Compound EF);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-acetamide, cis-isomer, (Compound EG);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-2-phenyl-acetamide, cis-isomer, (Compound EH);
cyclohexanecarboxylic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-amide, cis-isomer, (Compound EI);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-acetamide, trans-isomer, (Compound EJ);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-2-phenyl-acetamide, trans-isomer, (Compound EK);
cyclohexanecarboxylic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-amide, trans-isomer, (Compound EL);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-2-phenyl-acetamide, trans-isomer, (Compound EM);
4-{2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-butyric acid, cis-isomer, (Compound EN);
4-({2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-carbamoyl)-butyric acid, cis-isomer, (Compound EO);
4-{2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-propionic acid, cis-isomer, (Compound EP);
4-({2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-carbamoyl)-propionic acid, cis-isomer, (Compound EQ);
4-({2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-carbamoyl)-propionic acid, trans-isomer, (Compound ER);
N-{2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanesulphonamide, cis-isomer, (Compound ES);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-methanesulphonamide, cis-isomer, (Compound ET);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-benzenesulphonamide, cis-isomer, (Compound EU);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-C-phenyl-methanesulphonamide, cis-isomer, (Compound EV);
thiophene-2-sulphonic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-amide, cis-isomer, (Compound EW);
3,5-dimethyl-isoxazole-4-sulphonic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl-]-5-methyl-[1,3]dioxan-5-ylmethyl}-amide, cis-isomer, (Compound EX);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-methanesulphonamide, trans-isomer, (Compound EY);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-benzenesulphonamide, trans-isomer, (Compound EZ);
thiophene-2-sulphonic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-amide, trans-isomer, (Compound FA);
3,5-dimethyl-isoxazole-4-sulphonic acid {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-amide, trans-isomer, (Compound FB);
3-amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-propionamide, trans-isomer, (Compound FC);
3-amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-propionamide, cis-isomer, (Compound FD);
4-amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-butyramide, trans-isomer, (Compound FE);
4-amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-butyramide, cis-isomer, (Compound FF);
2-amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, trans-isomer, (Compound FG);
2-amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, cis-isomer, (Compound FH);
(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-ethyl-carbamic acid benzyl ester, trans-isomer, (Compound FI);
(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-ethyl-carbamic acid benzyl ester, cis-isomer, (Compound FJ);
(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-propyl-carbamic acid benzyl ester, trans-isomer, (Compound FK);
(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-propyl-carbamic acid benzyl ester, cis-isomer, (Compound FL);
(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-propyl-carbamic acid benzyl ester, trans-isomer, (Compound FM);
(3-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylcarbamoyl}-methyl-carbamic acid benzyl ester, cis-isomer, (Compound FN);
4-dimethylamino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-butyramide, cis- and trans-isomers, (Compound FO);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-benzamide, trans-isomer, (Compound FR);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-(4-hydroxy-piperdin-1-yl)-methanone, trans isomer, (Compound FS);
(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanone, trans isomer, (Compound FT);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carbamoyl}-piperidine-4-carboxylic acid ethyl ester, trans isomer, (Compound FU);
1-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carbamoyl}-piperidine-4-carboxylic acid, trans isomer, (Compound FV);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carbamoyl}-thiomorpholin-4-yl-methanone, trans isomer, (Compound FW);
(1,1-dioxothiomorpholin-4-yl)-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanone, trans isomer, (Compound FX);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carbamoyl}-(3-hydroxymethyl-piperidin-1-yl)-methanone, trans isomer, (Compound FY);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-(3-hydroxy-piperidin-1-yl)-methanone, trans isomer, (Compound FZ);
(2,6-dimethyl-morpholin-4-yl)-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanone, trans isomer, (Compound GA);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}--(3-hydroxy-pyrrolidin-1-yl)-methanone, trans isomer, (Compound GB);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-(4-methoxy-piperidin-1-yl)-methanone, trans isomer, (Compound GC);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone, trans isomer, (Compound GD);
{5-Amino-2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-[1,3]dioxan-5-yl}-methanol, cis isomer, (Compound LE);
{5-Amino-2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-[1,3]dioxan-5-yl}-methanol, trans isomer, (Compound LF);
{2-[4-(4-Fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-nitro-[1,3]dioxan-5-yl}-methanol, cis isomer, (Compound LG);
{2-[4-(4-Fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-nitro-[1,3]dioxan-5-yl}-methanol, trans isomer, (Compound LH);
C-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5,5-dimethyl-[1,3]dioxan-5-yl}-methylamine (Compound LI);
4-[2-(5,5-dimethyl-4-nitromethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine (Compound LJ);
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
A further particular group of compounds of the invention are those selected from the following:
{2-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans isomer, (Compound GE);
2-[5-(2-Amino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GI);
{(2-[5-(2-Dimethylamino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GJ);
(2-{4-(4-Fluoro-phenyl)-5-[2-(3-hydroxy-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound GK);
(2-{4-(4-Fluoro-phenyl)-5-[2-(2-methoxy-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl }-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound GL);
{2-[4-(4-Fluoro-phenyl)-5-(2-methylamino-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GM);
(2-{4-(4-Fluoro-phenyl)-5-[2-(1-ethoxycarbonylpiperidin-4-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound GN);
{2-[5-(2-Cyclohexylamino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GO);
(2-{4-(4-Fluoro-phenyl)-5-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound GP);
{2-[5-[2-(2-Amino-ethylamino)-pyrimidin-4-yl]-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GQ);
[2-(4-(4-Fluoro-phenyl)-5-{2-[3-(5H-imidazol-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidaxol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound GR);
(2-{4-(4-Fluoro-phenyl)-5-[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound GS);
2-[5-(2-Benzylamino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GT);
(2-{4-(4-Fluoro-phenyl)-5-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, R isomer, trans-isomer, (Compound GU);
(2-{4-(4-Fluoro-phenyl)-5-[2-(1-phenyl-ethylam ino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, S isomer, trans-isomer, (Compound GV);
{2-[4-(4-Fluoro-phenyl)-5-(2-phenylamino-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GW);
{2-[4-(4-Fluoro-phenyl)-5-(2-piperidin-1-yl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound GX);
[2-(4-(4-Fluoro-phenyl)-5-{2-[(pyridin-4-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound GY);
[2-(4-(4-Fluoro-phenyl)-5-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound GZ);
[2-(4-(4-Fluoro-phenyl)-5-{2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound HA);
[2-(4-(4-Fluoro-phenyl)-5-{2-[(furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-yl-)5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound HB);
[2-(4-(4-Fluoro-phenyl)-5-{2-[(thiophen-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound HC);
[2-(4-(4-Fluoro-phenyl)-5-{2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-morpholin-4-yl-methanone, trans-isomer, (Compound HD);
(2-{4-(4-Fluoro-phenyl)-5-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound HE);
{2-[4-(4-Fluoro-phenyl)-5-(2-morpholin-4-yl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound HF);
(2-{4-(4-Fluoro-phenyl)-5-[2-(3-methoxy-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound FG);
{2-[5-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yl]-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound HH);
{2-[5-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yl]-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound HI);
(4-{5-(4-Fluoro-phenyl)-2-[5-methyl-5-(morpholine-4-carbonyl)-[1,3]dioxan-2-yl]-3H-imidazol-4-yl}-pyrimidin-2-ylamino)-acetic acid, trans-isomer, (Compound HJ);
3-(4-{5-(4-Fluoro-phenyl)-2-[5-methyl-5-(morpholine-4-carbonyl)-[1,3]dioxan-2-yl]-3H-imidazol-4-yl}-pyrimidin-2-ylamino)-propionic acid, trans-isomer, (Compound HK);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamine, (Compound HL);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-methyl-amine, (Compound HM);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-dimethyl-amine, (Compound HN);
cyclopropyl-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-amine, (Compound HO);
cyclohexyl-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-amine, (Compound HQ);
2-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamino}-ethanol, (Compound HR);
N1-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-ethane-1,2-diamine, (Compound HS);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-3(5H-imidazol-1-yl)-propyl]-amine, (Compound HT);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(3-morpholin-4-yl-propyl)-amine, (Compound HU);
3-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamino}-propan-1-ol, (Compound HV);
benzyl-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-amine, (Compound HW);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(1-phenyl-ethyl)-amine, R-isomer, (Compound HX);
{4-[2-(5,5dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(1-phenyl-ethyl)-amine, S-isomer, (Compound HY);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(1-phenyl-amine, (Compound HZ);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl-pyrimidine, (Compound IA);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-pyridin-4-ylmethyl-amine, (Compound IB);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-pyridin-2-ylmethyl-amine, (Compound IC);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-pyridin-3-ylmethyl-amine, (Compound ID);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(furan-2-ylmethyl)-amine, (Compound IE);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(thiophen-2-ylmethyl)-amine, (Compound IF);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(tetrahydro-furan-2-ylmethyl)-amine, (Compound IG);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-2-(4-methyl-piperazin-1-yl)-pyrimidine, (Compound IH);
4-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-morpholine, (Compound IJ);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-propyl)-amine, (Compound IK);
{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(2-methoxy-ethyl)-amine, (Compound IL);
N-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-Nxe2x80x2,Nxe2x80x2-dimethyl-propane-1,3-diamine, (Compound IM);
N-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-Nxe2x80x2,Nxe2x80x2-dimethyl-ethane-1,2-diamine, (Compound IN);
{2-[5-(2-amino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, trans-isomer, (Compound IO)
{2-[4-(4-Fluoro-phenyl)-5-(2-methoxy-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound IP);
{2-[5-(2-Benzyloxy-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound IQ);
{2-[4-(4-Fluoro-phenyl)-5-(2-phenoxy-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound IR);
(2-{4-(4-Fluoro-phenyl)-5-[2-(2-methoxy-ethoxy)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans-isomer, (Compound IS);
{2-[5-[2-(2-Dimethylamino-ethoxy)-pyrimidin-4-yl]-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound IT);
{2-[5-(2-Cyclohexyloxy-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound IU);
{2-[5-(2-Isopropoxy-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound IW);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-2-methoxy-pyrimidine, (Compound IY);
2-benzyloxy-4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine, (Compound IZ);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-2-phenoxy-pyrimidine, (Compound JA);
4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-2-(2-methoxy-ethoxy)-pyrimidine, (Compound JB);
(2-{4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yloxy}-ethyl)-dimethyl-amine, (Compound JC);
2-cyclohexyloxy-4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine, (Compound JD);
2-isopropoxy-4-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine, (Compound JE);
4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-ylamine, cis-isomer, (Compound JF);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-methyl-amine, cis-isomer, (Compound JG);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-dimethyl-amine, cis-isomer, (Compound JH);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-cyclopropyl-amine, cis-isomer, (Compound JI);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-piperidin-4-yl-amine, cis-isomer, (Compound JJ);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-cyclohexyl-amine, cis-isomer, (Compound JK);
2-{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-ylamino}-ethanol, cis-isomer, (Compound JL);
N1-{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-ethane-1,2-diamine, cis-isomer, (Compound JM);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-[3-(5H-imidazol-1-yl)-propyl]-amine, cis-isomer, (Compound JN);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(3-morpholin-4-yl-propyl)-amine, cis-isomer, (Compound JO);
3-{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-ylamino}-propan-1-ol, cis-isomer, (Compound JP);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-benzyl-amine, cis-isomer, (Compound JQ);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(1-phenyl-ethyl)-amine, R isomer, cis-isomer, (Compound JR);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(1-phenyl-ethyl)-amine, S isomer, cis-isomer, (Compound JS);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-phenyl-amine, cis-isomer, (Compound JT);
2-[4-(4-fluoro-phenyl)-5-(2-piperidin-1-yl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylamine, cis-isomer, (Compound JU);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-pyridin-4-ylmethyl-amine, cis-isomer, (Compound JV);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-pyridin-2-ylmethyl-amine, cis-isomer, (Compound JW);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-pyridin-3-ylmethyl-amine, cis-isomer, (Compound JX);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(furan-2-ylmethyl)-amine , cis-isomer, (Compound JY);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(thiophen-2-ylmethyl)-amine, cis-isomer, (Compound JZ);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(tetrahydro-furan-2-ylmethyl)-amine, cis-isomer, (Compound KA);
2-{4-(4-fluoro-phenyl)-5-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-ylamine, cis-isomer, (Compound KB);
2-[4-(4-fluoro-phenyl)-5-(2-morpholin-4-yl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylamine, cis-isomer, (Compound KC);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(3-methoxy-propyl)-amine, cis-isomer, (Compound KD);
{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-(2-methoxy-ethyl)-amine, cis-isomer, (Compound KE);
N-{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-Nxe2x80x2,Nxe2x80x2-dimethyl-propane-1,3-diamine, cis-isomer, (Compound KF);
N-{4-[2-(5-amino-5-methyl-[1,3]dioxan-2-yl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-Nxe2x80x2,Nxe2x80x2-dimethyl-ethane-1,2-diamine, cis-isomer, (Compound KG);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans isomer, (Compound KH);
2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonylpyrimidin-4-yl)-1H-imidazol-2-yl]-5,5-dimethyl-[1,3]dioxan (Compound KI);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, trans-isomer (Compound KJ);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, cis-isomer (Compound KK);
2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methylene-[1,3]dioxane (Compound KL).
4-[2-[1,3]dioxan-2-yl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-2-methylsulphonyl-pyrimidine (Compound KM);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-[1,3]dioxan-5-yl}-methanol, trans-isomer (Compound KN);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphonyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-[1,3]dioxan-5-yl}-methanol, cis-isomer (Compound KO);
2,2,2-trifluoro-N-[2-{4-(4-fluoro-phenyl)-5-(2-methanesulphonylpyrimidin-4-yl)-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl]acetamide, cis-isomer (Compound KP);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphanylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans isomer, (Compound KQ);
2-[4-(4-fluoro-phenyl)-5-(2-methylsulphanylpyrimidin-4-yl)-1H-imidazol-2-yl]-5,5-dimethyl-[1,3]dioxane (Compound KR);
2,2,2-trifluoro-N-[2-{4-(4-fluoro-phenyl)-5-(2-methylsulphanyl-pyrimidin-4-yl)-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl]acetamide, cis-isomer, (Compound KS);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, cis isomer (Compound KT);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, trans isomer (Compound KU);
4-[5-(4-fluoro-phenyl)-2-(5-methylene-[1,3]dioxan-2-yl)-3H-imidazol-4-yl]-2-methylsulfanyl-pyrimidine (Compound KV);
4-[2-[1,3]dioxan-2-yl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-2-methylsulphanyl-pyrimidine (Compound KW);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-[1,3]dioxan-5-yl}-methanol, trans-isomer (Compound KX);
{2-[4-(4-fluoro-phenyl)-5-(2-methylsulphanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-[1,3]dioxan-5-yl}-methanol, cis-isomer (Compound KY);
C-{2-[4-(4-fluoro-phenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methylamine, cis isomer (Compound KZ);
2-[4-(4-fluoro-phenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carboxylic acid amide, cis isomer Compound LA);
2-[4-(4-fluoro-phenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carboxylic acid, cis isomer (Compound LB);
2-[4-(4-fluorophenyl)-5-(2-methylsulphanylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carboxylic acid methyl ester, trans isomer, (Compound LC);
2-[4-(4-fluorophenyl)-5-(2-methylsulphanylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carboxylic acid methyl ester, cis isomer, (Compound LD);
2,2,2-trifluoro-N-{2-[5-(2-methylsulphonyl-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-acetamide, cis isomer, (Compound LK);
2,2,2-trifluoro-N-{2-[5-(2-methylsulphonyl-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-ylmethyl}-acetamide, trans isomer, (Compound LL);
2-[4-(4-fluorophenyl)-5-(2-methylsulphonylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carboxylic acid methyl ester, trans isomer, (Compound LM);
2-[4-(4-fluorophenyl)-5-(2-methylenesulphonylpyrimidin-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-carboxylic acid methyl ester, cis isomer (Compound LN);
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Preferred compounds of the invention include:
{2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-methanol, cis-isomer, (Compound A);
C-[5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-yl]-methylamine, cis- and trans-isomers, (Compound D);
4-[5-(4-fluoro-phenyl)-2-(4-isopropyl-5,5-dimethyl-[1,3]dioxan-2-yl)-3H-imidazol-4-yl]-pyridine, (R/S)(R/S) isomers, (Compound T);
C-[5-methyl-2-(5-phenyl-4-pyridin-4-yl-1H-imidazol-2-yl)-[1,3]dioxan-5-yl]-methylamine, trans-isomer, (Compound AA);
C-[5-methyl-2-(5-phenyl-4-pyridin-4-yl-1H-imidazol-2-yl)-[1,3]dioxan-5-yl]-methylamine, cis-isomer, (Compound AB);
5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylamine, cis-isomer, (Compound AE);
5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylamine, trans-isomer, (Compound AF);
5-methyl-2-{5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-2-yl}-[1,3]dioxan-5-ylamine, cis- and trans-isomers, (Compound AG);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid amide, trans-isomer, (Compound AN);
{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound AW);
2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid amide, cis-isomer, (Compound BM);
amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, trans-isomer, (Compound FC);
amino-N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-acetamide, cis-isomer, (Compound FD);
N-{2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-benzamide, trans-isomer, (Compound FR);
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Further preferred compounds of the invention include:
{2-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans isomer, (Compound GE);
(2-{4-(4-fluoro-phenyl)-5-[2-(2-methoxy-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans isomer, (Compound GI);
2-{4-(4-fluoro-phenyl)-5-[2-(1-ethoxycarbonylpiperidin-4-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxan-5-yl)-morpholin-4-yl-methanone, trans isomer, (Compound GK);
{2-[5-(2-cyclohexylamino-pyrimidin-4-yl)-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans isomer, (Compound GL);
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
A particularly preferred compound of the invention is {2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-5-yl}-morpholin-4-yl-methanone, trans-isomer, (Compound AW); and the corresponding N-oxide, and its prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of this compound and its N-oxide and prodrugs, especially its methane sulphonic acid salt as depicted by Compound FP.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention are inhibitors of the generation of tumour necrosis factor (TNF), especially TNF-alpha, according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, especially of TNF-alpha. For example, compounds of the present invention are useful in the treatment of joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds are useful in the treatment of acute synovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter""s syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, gout, toxic shock syndrome, chronic pulmonary inflammatory diseases including asthma and adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, bone resorption diseases, osteoporosis, restenosis, heart failure and myocardial ischaemic syndromes, cardiac and renal reperfusion injury, thrombosis, glomerulamephritis, graft vs. host reaction, allograft rejection and leprosy. Furthermore, the compounds are useful in the treatment of infections such as viral infections, for example HIV, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, parasitic infections, for example malaria such as cerebral malaria, and yeast and fungal infections, for example fungal meningitis; fever and myalgias due to infection; AIDS; AIDS related complex (ARC); cachexia secondary to infection or malignancy; cachexia secondary to acquired immune deficiency syndrome (AIDS) or to. cancer; keloid and scar tissue formation; pyresis; diabetes; inflammatory bowel diseases such as Crohn""s disease and ulcerative colitis; eczema; contact dermititis; psoriasis; sunburn and conjunctivitis.
Compounds of the invention are also useful in the treatment of diseases of, or injury to, the brain in which over-production of TNF-alpha has been implicated, such as multiple sclerosis, Alzheimers disease, trauma, stroke and other ischaemic conditions.
Compounds of the invention may also be useful in inhibiting diseases associated with over-production of other pro-inflammatory cytokines, IL-1, IL-6 and IL-8.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, especially TNF-alpha, for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting TNF and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended.in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
Compounds of the invention may be prepared by methods similar to those described in EP424195 and EP506437.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of this invention may be represented by the formula (Ic): 
wherein R4, R5, R6 and m are as hereinbefore defined and T1 represents a group of the formula: 
wherein R1, R2 and R3 are as hereinbefore defined.
In a process (A), compounds of formula (I), wherein R1, R2, R4, R5, R6 and m are as hereinbefore defined and R3 is hydrogen, may be prepared by reaction of compounds of formula (II): 
wherein R1 and R2 are as hereinbefore defined, R19 is hydrogen or a suitable protecting group, such as 2-trimethylsilanyl-ethoxymethyl, which is subsequently removed under the acidic reaction conditions and R20 is xe2x80x94CHO or xe2x80x94CH(OMe)2, with compounds of formula (III): 
wherein R4, R5, R6 and m are as hereinbefore defined. The reaction may conveniently be carried out in the presence of an acid catalyst, such as pyridinium 4-toluene sulphonate or 4-toluene sulphonic acid, in an inert solvent, such as toluene, at reflux temperature, with azeotropic removal of the water formed in the reaction.
Compounds of formula (I), wherein R1, R2, R4, R5, R6 and m are as hereinbefore defined and R3 represents a group xe2x80x94L1xe2x80x94R7 (where L1 and R7 are as hereinbefore defined) or xe2x80x94L2xe2x80x94R8 (where L2 is as hereinbefore defined and R8 is aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl) may be similarly prepared by reaction of compounds of formula (II), wherein R1, R2 are as hereinbefore defined, R19 represents a group xe2x80x94L1xe2x80x94R7 (where L1 and R7 are as hereinbefore defined) or xe2x80x94L2xe2x80x94R8 (where L2 is as hereinbefore defined and R8 is aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl) and R20 is xe2x80x94CHO or xe2x80x94CH(OMe)2, with compounds of formula (III) wherein R4, R5, R6 and m are as hereinbefore defined.
In a process B, compounds of formula (I), wherein R2, R3, R4, R5, R6 and m are as hereinbefore defined, and R1 represents a group (IV): 
wherein R18 is Y4Y5Nxe2x80x94 (in which Y4 and Y5 are as hereinbefore defined), may be prepared by:
(i) treating Merrifield resin (chloromethylpolystyrene resin) with potassium thioacetate in an inert solvent, such as dimethylformamide, at a temperature at about room temperature, to give Resin A; 
(ii) reaction of Resin A with lithium borohydride in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature, to give Resin B; 
(iii) reaction of Resin B with an alkali metal hydride, such as sodium hydride, in an inert solvent, such as dimethylformamide, at a temperature at about room temperature, followed by treatment with compounds of formula (V); 
wherein R2, R3, R4, R5, R6 and m are as hereinbefore defined, at a temperature from about room temperature to about 80xc2x0 C., to give Resin C; 
in which R2, R3, R4, R5, R6 and m are as hereinbefore defined; followed by appropriate functional group interconversions, for example those described hereinafter.
(iv) reaction of Resin C, in which R2, R3, R4, R5, R6 and m are as hereinbefore defined, with m-chloroperoxybenzoic acid, in an inert solvent or preferably in a mixture of inert solvents, such as a mixture of dichloromethane and methanol, to give resin D, in which R2, R3, R4, R5, R6 and m are as hereinbefore defined; 
(v) reaction of Resin D, wherein R2, R3, R4, R5, R6 and m are as hereinbefore defined, with amines of formula HNY4Y5, wherein Y4 and Y5 are as hereinbefore defined, in an inert solvent, such as dimethoxyethane, and at a temperature at about 70xc2x0 C.
Compounds of formula (I), wherein R2, R3, R4, R5, R6 and m are as hereinbefore defined and R1 represents a group (IV), wherein R18 is a xe2x80x94OR17 or xe2x80x94SR17 group (in which R17 is as hereinbefore defined), may be prepared by reaction of Resin D, wherein R2, R3, R4, R5, R6 and m are as hereinbefore defined, with compounds of formula R17OH or R17SH (in which R17 is as hereinbefore defined), in the presence of an alkali metal hydride, such as sodium hydride, in an inert solvent, such as dimethylformamide, and at a temperature from about room temperature to about 80xc2x0 C.
According to a further feature of the present invention, compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of formula (I), wherein R1, R2, R4, R5, R6 and m are as hereinbefore defined and R3 is a group xe2x80x94L1xe2x80x94R7 (in which L1 represents a straight- or branched-chain alkylene linkage containing from 1 to about 6 carbon atoms and R7 is as hereinbefore defined), may be prepared by alkylation of compounds of formula (I) wherein R1, R2, R4, R5, R6 and m are as hereinbefore defined and R3 is hydrogen, with an alkyl halide of formula (IV):
X1xe2x80x94L1xe2x80x94R7xe2x80x83xe2x80x83(IV)
wherein L1 and R7 are as hereinbefore defined immediately above and X1 is a halogen atom, preferably a bromine atom. The alkylation may for example be carried out in the presence of a base, such as an alkali metal hydride, e.g. sodium hydride, in dimethylformamide, or dimethyl sulphoxide, at a temperature from about 0xc2x0 C. to about 100xc2x0 C.
As another example of the interconversion process, compounds of formula (I), wherein R1, R2, R4, R5, R6 and m are as hereinbefore defined and R3 is a group xe2x80x94L2xe2x80x94R8 (in which L2 represents a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms and contains a double or triple carbon-carbon bond, and R8 is aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl), may be similarly prepared by alkylation of compounds of formula (I), wherein R1, R2, R4, R5, R6 and m are as hereinbefore defined and R3 is hydrogen, with compounds of formula (V):
xe2x80x83X1xe2x80x94L2xe2x80x94R8xe2x80x83xe2x80x83(V)
wherein L2 and R8 are as hereinbefore defined immediately above and X1 is a halogen atom, preferably a bromine atom.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NH2 group, may be prepared by reaction of compounds of formula (Ic) wherein T1, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94NHC(xe2x95x90O)CF3 group, with a base such as potassium or ammonium carbonate in methanol, or a mixture of methanol and water, at a temperature at about reflux temperature.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94N(R10)xe2x80x94C(xe2x95x90O)xe2x80x94R15 or xe2x80x94N(R10)xe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 group (in which R10, R15, R16 and L4 are as hereinbefore defined), may be prepared by reaction of compounds of formula (Ic) wherein T1, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94NHR10 group (in which R10 is as hereinbefore defined), with the appropriately substituted acid chloride Clxe2x80x94C(xe2x95x90O)xe2x80x94R15 or Clxe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined) in the presence of triethylamine in an inert solvent such as tetrahydrofuran and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R15 or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 group (in which R15, R16 and L4 are as hereinbefore defined), may be prepared by reaction of compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94NH2 group, with the appropriately substituted acid HOxe2x80x94C(xe2x95x90O)xe2x80x94R15 or HOxe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined) respectively, in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature. Other standard peptide coupling procedures may be employed for the reaction, such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, or treatment with 1-hydroxybenzotriazole and a carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, in an inert solvent such as dimethylformamide and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R15 or a xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 group (in which R15, R16 and L4 are as hereinbefore defined), may be prepared by reaction of compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4contains a xe2x80x94NH2 group, with the appropriately substituted acid anhydride R15xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R15 or R16xe2x80x94L4xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined) in the presence of triethylamine or pyridine, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94R15 or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94L4xe2x80x94R16 group (in which R15, R16 and L4 are as hereinbefore defined), may be prepared by reaction of compounds of formula (Ic) wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NH2 group, with the appropriately substituted isocyanate Oxe2x95x90Cxe2x95x90Nxe2x80x94R15 or Oxe2x95x90Cxe2x95x90Nxe2x80x94L4xe2x80x94R16 (in which R15, R16and L4 are as hereinbefore defined), in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (Ic) wherein T1, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94NHxe2x80x94(Cxe2x95x90S)xe2x80x94NHxe2x80x94R15 or xe2x80x94NHxe2x80x94(Cxe2x95x90S)xe2x80x94NHxe2x80x94L4xe2x80x94R16 group (in which R15, R16 and L4 are as hereinbefore defined), may prepared by reaction of compounds of formula (Ic) wherein T1, R5, R6 and m are as hereinbefore defined, and R4contains a xe2x80x94NH2 group, with the appropriately substituted isothiocyanate Sxe2x95x90Cxe2x95x90Nxe2x80x94R15 or Sxe2x95x90Cxe2x95x90Nxe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined), in an inert solvent, such as tetrahydrofuran, and at a temperature at about reflux temperature.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m re as hereinbefore defined and R4 contains a xe2x80x94CO2H group, may be prepared by hydrolysis of corresponding compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94CO2R21 group (in which R21 is as hereinbefore defined). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide or carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94C(xe2x95x90O)xe2x80x94NY4Y5 group (in which Y4 and Y5 are as hereinbefore defined), may be prepared by reaction of compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94CO2H group, with an appropriately substituted amine of formula HNY4Y5 (in which Y4 and Y5 are as hereinbefore defined). The coupling reaction may conveniently be carried out in the presence of 1-hydroxybenzotriazole and a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in an inert solvent such as dimethylformamide and at a temperature at about room temperature. Alternatively the reaction may be carried out by initial conversion of the acid of formula (Ic), wherein R4 contains a xe2x80x94CO2H group, to the corresponding acid chloride (for example by reaction with thionyl chloride or oxalyl chloride at room temperature) followed by treatment with an appropriately substituted amine of formula HNY4Y5.
As another example of the interconversion process, compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0xc2x0 C. and room temperature. This latter method is preferred for compounds containing an acid-labile group.
As another example of the interconversion process, compounds of formula (Ic), wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15 or xe2x80x94N(R10)xe2x80x94SO2xe2x80x94L4xe2x80x94R16 group (in which R10, R15, R16 and L4 are as hereinbefore defined), may be prepared from the corresponding compounds of of formula (Ic) wherein T1, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NH2 group by treatment with the appropriately substituted acid chloride Clxe2x80x94SO2xe2x80x94R15 or Clxe2x80x94SO2xe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined), in the presence of a suitable base, such as triethylamine, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 or sulphoxide linkages. For example, compounds of formula (Ib) where R18 is xe2x80x94SO2Me may conveniently be prepared by means of reaction of compounds of formula (Ib) where R18 is xe2x80x94SMe with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, such as dichloromethane, at a temperature from about 0xc2x0 C. to about room temperature.
As another example of the interconversion process, compounds of formula (Ib), wherein R4 and R5 are as hereinbefore defined and R18 is a xe2x80x94NY4Y5 group (in which Y4 is hydrogen and Y5 is as hereinbefore defined), may be prepared by reaction of compounds of formula (Ib), where R18 is a xe2x80x94SO2Me group, with an appropriately substituted amine of formula Y5NH2 (in which Y5 is as hereinbefore defined). The reaction may conveniently be carried out in an inert solvent such as dimethylformamide at a temperature up to about 100xc2x0 C. When Y5 is hydrogen the reaction may be conveniently carried out in a sealed vessel. When Y5 is aryl, for example phenyl, the reaction may be conveniently carried out with the lithio-anion of the amine.
As another example of the interconversion process, compounds of formula (Ib), wherein R4 and R5 are as hereinbefore defined and R18 is a xe2x80x94OR17 group (in which R17 is as hereinbefore defined), may be prepared by reaction of compounds of formula (Ib), where R18 is a xe2x80x94SO2Me group, with an appropriately substituted alcohol of formula R17OH (in which R17 is as hereinbefore defined). The reaction may conveniently be carried out in the presence of an alkali metal hydride, such as sodium hydride, in a mixture of inert solvents, for example tetrahydrofuran and dimethylformamide, and at a temperature at about room temperature.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or an aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, such as tetrahydrofuran, in which case the salt separates directly or can be obtained by concentration of the solution.
Compounds of this invention can be regenerated from their acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from water.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Intermediates of formula (II), wherein R1 and R2 are as hereinbefore defined, R19 is a 2-trimethylsilanyl-ethoxymethyl group and R20 is xe2x80x94CH(OMe)2, may be prepared by reaction of compounds of formula (II), wherein R1 and R2 are as hereinbefore defined, R19 is a 2-trimethylsilanyl-ethoxymethyl group and R20 is xe2x80x94CHO, with trimethylorthoformate in the presence of an acid catalyst, such as 4-toluene sulphonic acid, in methanol at reflux temperature.
Intermediates of formula (II), wherein R1 and R2 are as hereinbefore defined, R19 is a 2-trimethylsilanyl-ethoxymethyl group and R20 is xe2x80x94CHO, may be prepared by reaction of compounds of formula (1): 
wherein R1 and R2 are as hereinbefore defined, R19 is a 2-trimethylsilanyl-ethoxymethyl group, with an alkyllithium, such as butyllithium or lithium diisopropylamide, in an inert solvent, such as tetrahydrofuran, at a temperature at about xe2x88x9278xc2x0 C., followed by reaction with N-formylmorpholine.
Intermediates of formula (II), wherein R1 and R2 are as hereinbefore defined, R19 is hydrogen and R20 is xe2x80x94CH(OMe)2, may be prepared by reaction of compounds of formula (2): 
wherein R1 and R2 are as hereinbefore defined, with glyoxal 1,1-dimethylacetal and ammonium acetate. The reaction may conveniently be carried out in a mixture of inert solvents, such as tert-butylmethyl ether and methanol, and at a temperature at about room temperature.
Intermediates of formula (II), wherein R1, R2 are as hereinbefore defined, R19 represents a xe2x80x94L1xe2x80x94R7or xe2x80x94L2xe2x80x94R8 group (in which R7, L1 and L2 is as hereinbefore defined and R8 is aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl) and R20 is xe2x80x94CHO, may be similarly prepared by reaction of compounds of formula (1), wherein R1, R2 and R19 are as defined immediately above, with butyl lithium followed by reaction with N-formylmorpholine.
Intermediate 1,3-propanediols of formula (III), wherein R4 is an azidomethyl group, R5 is a methyl group, R6 is hydrogen and m is 1, and where both R4 and R5 are attached in the 2-position, may be prepared by reaction of 5-azidomethyl-2,5-dimethyl-1,3-dioxane (prepared according to the procedure in J.Org.Chem., 1992, 57, page 6080) with a mineral acid, for example hydrochloric acid, in an aqueous organic solvent mixture such as tetrahydrofuran and water, at reflux temperature.
Intermediate 1,3-propanediols of formula (III), wherein R4 is an xe2x80x94NHC(xe2x95x90O)CF3 group, R5 is a methyl group, R6 is hydrogen and m is 1, and where both R4 and R5 are attached in the 2-position, may be prepared by reaction of 2-amino-2-methyl-1,3-propanediol with trifluoroacetic acid in the presence of a base, such as potassium carbonate, in an inert solvent, such as dimethylformamide, and at a temperature at about room temperature.
Intermediate 1,3-propanediols of formula (III), wherein R4 is a xe2x80x94C(xe2x95x90O)xe2x80x94NY4Y5 group (in which Y4 and Y5 are as hereinbefore defined), R5 is a methyl group, R6 is hydrogen and m is 1, and where both R4 and R5 are attached in the 2-position, may be prepared by reaction of 2-carboxy-2-methyl-1,3-propanediol with an amine of formula HNY4Y5, wherein Y4 and Y5 are as hereinbefore defined. The coupling may conveniently be carried out with a carbodiimide, such as dicyclohexylcarbodiimide, in the presence of 1-hydroxybenzotriazole and disisopropylethylamine, in an inert solvent, such as acetonitrile, and at a temperature from room temperature to about 55xc2x0 C. Other standard peptide coupling procedures may be employed for the reaction, such as those described hereinbefore.
Resins of formula Resin C in which R3, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94C(xe2x95x90O)xe2x80x94NY4Y5 group may be prepared from the corresponding Resin C, in which R3, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94C(xe2x95x90O)xe2x80x94OR21 group (in which R21 is alkyl, aryl or arylalkyl), by: (i) treatment with an alkali metal hydroxide, such as sodium hydroxide, in a mixture of water and a water miscible inert organic solvent, such as tetrahydrofuran,and at a temperature from about room temperature to about 70xc2x0 C.; (ii) treatment of the resulting resin in which R4 contains a xe2x80x94C(xe2x95x90O)xe2x80x94OH group with oxalyl chloride solution in an inert solvent, such as dichloromethane, at a temperature at about room temperature; (iii) treatment of the resulting resin in which R4 contains a xe2x80x94C(xe2x95x90O)xe2x80x94Cl group with an amine of formula HNY4Y5 in an inert solvent, such as dichloromethane, at a temperature at about room temperature.
Resins of formula Resin C in which R3, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94N(R10)xe2x80x94C(xe2x95x90O)xe2x80x94R15 or xe2x80x94N(R10)xe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 group (in which R10, R15, R16 and L4 are as hereinbefore defined), may be prepared from the corresponding Resin C, in which R3, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NH2 group by treatment with the appropriately substituted acid chloride Clxe2x80x94C(xe2x95x90O)xe2x80x94R15 or Clxe2x80x94C(xe2x95x90O)xe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined), in the presence of triethylamine, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
Resins of formula Resin C in which R3, R5, R6 and m are as hereinbefore defined, and R4 contains a xe2x80x94N(R10)xe2x80x94SO2xe2x80x94R15 or xe2x80x94N(R10)xe2x80x94SO2xe2x80x94L4xe2x80x94R16 group (in which R10, R15, R16 and L4 are as hereinbefore defined), may be prepared from the corresponding Resin C, in which R3, R5, R6 and m are as hereinbefore defined and R4 contains a xe2x80x94NH2 group by treatment with the appropriately substituted acid chloride Clxe2x80x94SO2xe2x80x94R15 or Clxe2x80x94SO2xe2x80x94L4xe2x80x94R16 (in which R15, R16 and L4 are as hereinbefore defined), in the presence of triethylamine, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
Compounds of formula (1), wherein R1 and R2 are as hereinbefore defined, R19 is a 2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction of compounds of formula (1), wherein R1 and R2 are as hereinbefore defined, R19 is a hydrogen atom, with 2-(trimethylsilyl)ethoxymethyl chloride in the presence of sodium hydride, in an inert solvent such as dimethylformamide, and at a temperature at about room temperature.
Compounds of formula (1) wherein R1 and R2 are as hereinbefore defined, R19 represents a group xe2x80x94L1xe2x80x94R7 (where L1 and R7 are as hereinbefore defined) or xe2x80x94L2xe2x80x94R8 (where L2 is as hereinbefore defined and R8 is aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl) may be similarly prepared by reaction of compounds of formula (1), wherein R1 and R2 are as hereinbefore defined, R19 is a hydrogen atom, with an alkyl halide of formula (V) or (VI) respectively, in the presence of sodium hydride.
Compounds of formula (1), wherein R1 and R2 are as hereinbefore defined, R19 is a hydrogen atom, may be prepared by the application or adaptation of known literature methods, for example Boehm et. al., J.Med.Chem., 1996, 39, page 3829.
Intermediates of formulae (II), (III), (IV), Resin C and Resin D are novel compounds and, as such, they and their processes described herein for their preparation constitute further features of the present invention.